Skip to main content

Advertisement

SpringerLink
Log in

Non-Peptidergic Nociceptive Neurons Are Essential for Mechanical Inflammatory Hypersensitivity in Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ATF-3:

Activating transcription factor 3

AUC:

Area under the curve

BSA:

Bovine serum albumin

cAMP:

Cyclic adenosine monophosphate

CGRP:

Calcitonin-gene related peptide

DRG:

Dorsal root ganglion

EP:

E prostanoid receptor

g:

Grams

GDNF:

Glial cell-derived neurotrophic factor

GFRα-1:

GDNF family receptor alpha 1

GPCR:

G protein-coupled receptor

HCN:

Hyperpolarization-activated cyclic nucleotide-gated

HTMRs:

High-threshold mechanoreceptors

IB4:

Isolectin B4

IB4-Sap:

IB4-saporin

i.pl.:

Intraplantar

i.t.:

Intrathecal

LTMRs:

Low-threshold mechanoreceptors

MCP-1:

Monocyte chemoattractant protein 1

Nav :

Voltage-gated sodium ion channel

NGF:

Nerve growth factor

OCT:

Optimum cutting temperature

PBS:

Phosphate-buffered saline

P2X3 :

Purinoceptor 3

PFA:

Paraformaldehyde

PGE2 :

Prostaglandin E2

PKA:

Protein kinase A

PKCε:

Epsilon isozyme of protein kinase C

Sap:

Unconjugated saporin

SEM:

Standard error of the mean

T-PER:

Tissue protein extraction reagent

TrkA:

Tropomyosin receptor kinase A

TRPV1:

Transient receptor potential cation channel subfamily V member 1

WT:

Wild type

References

  1. Basbaum A, Jessel T (2000) The perception of pain. Principles of neural science, fourth edition edn. McGraw-Hill, New York

    Google Scholar 

  2. Meyer R, Ringkamp M, Campbell J, Raja S (2013) Peripheral mechanisms of cutaneous nociception. Wall and Melzack's textbook of pain, Sixth edn. Elsevier, Philadelphia

    Google Scholar 

  3. Snider WD, McMahon SB (1998) Tackling pain at the source: new ideas about nociceptors. Neuron 20(4):629–632

    Article  CAS  PubMed  Google Scholar 

  4. Molliver DC, Radeke MJ, Feinstein SC, Snider WD (1995) Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections. J Comp Neurol 361(3):404–416. https://doi.org/10.1002/cne.903610305

    Article  CAS  PubMed  Google Scholar 

  5. Verge VM, Richardson PM, Benoit R, Riopelle RJ (1989) Histochemical characterization of sensory neurons with high-affinity receptors for nerve growth factor. J Neurocytol 18(5):583–591

    Article  CAS  PubMed  Google Scholar 

  6. Verge VM, Riopelle RJ, Richardson PM (1989) Nerve growth factor receptors on normal and injured sensory neurons. J Neurosci 9(3):914–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bennett DL, Michael GJ, Ramachandran N, Munson JB, Averill S, Yan Q, McMahon SB, Priestley JV (1998) A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci 18(8):3059–3072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Molliver DC, Snider WD (1997) Nerve growth factor receptor TrkA is down-regulated during postnatal development by a subset of dorsal root ganglion neurons. J Comp Neurol 381(4):428–438

    Article  CAS  PubMed  Google Scholar 

  9. Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, Wen D, Yan Q, Snider WD (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19(4):849–861

    Article  CAS  PubMed  Google Scholar 

  10. Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45(1):17–25. https://doi.org/10.1016/j.neuron.2004.12.015

    Article  CAS  PubMed  Google Scholar 

  11. Tarpley JW, Kohler MG, Martin WJ (2004) The behavioral and neuroanatomical effects of IB4-saporin treatment in rat models of nociceptive and neuropathic pain. Brain Res 1029(1):65–76. https://doi.org/10.1016/j.brainres.2004.09.027

    Article  CAS  PubMed  Google Scholar 

  12. Bogen O, Dina OA, Gear RW, Levine JD (2009) Dependence of monocyte chemoattractant protein 1 induced hyperalgesia on the isolectin B4-binding protein versican. Neuroscience 159(2):780–786. https://doi.org/10.1016/j.neuroscience.2008.12.049

    Article  CAS  PubMed  Google Scholar 

  13. Joseph EK, Levine JD (2010) Hyperalgesic priming is restricted to isolectin B4-positive nociceptors. Neuroscience 169(1):431–435. https://doi.org/10.1016/j.neuroscience.2010.04.082

    Article  CAS  PubMed  Google Scholar 

  14. Alvarez P, Gear RW, Green PG, Levine JD (2012) IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. Exp Neurol 233(2):859–865. https://doi.org/10.1016/j.expneurol.2011.12.019

    Article  CAS  PubMed  Google Scholar 

  15. Joseph EK, Chen X, Bogen O, Levine JD (2008) Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 9(5):463–472. https://doi.org/10.1016/j.jpain.2008.01.335

    Article  CAS  PubMed  Google Scholar 

  16. Ye Y, Dang D, Viet CT, Dolan JC, Schmidt BL (2012) Analgesia targeting IB4-positive neurons in cancer-induced mechanical hypersensitivity. J Pain 13(6):524–531. https://doi.org/10.1016/j.jpain.2012.01.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. La JH, Feng B, Kaji K, Schwartz ES, Gebhart GF (2016) Roles of isolectin B4-binding afferents in colorectal mechanical nociception. Pain 157(2):348–354. https://doi.org/10.1097/j.pain.0000000000000380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ye Y, Bae SS, Viet CT, Troob S, Bernabé D, Schmidt BL (2014) IB4(+) and TRPV1(+) sensory neurons mediate pain but not proliferation in a mouse model of squamous cell carcinoma. Behav Brain Funct 10:5. https://doi.org/10.1186/1744-9081-10-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67(2–3):313–316

    Article  CAS  PubMed  Google Scholar 

  20. Cunha TM, Verri WA, Vivancos GG, Moreira IF, Reis S, Parada CA, Cunha FQ, Ferreira SH (2004) An electronic pressure-meter nociception paw test for mice. Braz J Med Biol Res 37(3):401–407

    Article  CAS  PubMed  Google Scholar 

  21. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    Article  CAS  PubMed  Google Scholar 

  22. Sakurada T, Katsumata K, Tan-No K, Sakurada S, Kisara K (1992) The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord. Neuropharmacology 31(12):1279–1285

    Article  CAS  PubMed  Google Scholar 

  23. Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387(6632):505–508. https://doi.org/10.1038/387505a0

    Article  CAS  PubMed  Google Scholar 

  24. Tsujino H, Kondo E, Fukuoka T, Dai Y, Tokunaga A, Miki K, Yonenobu K, Ochi T et al (2000) Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury. Mol Cell Neurosci 15(2):170–182. https://doi.org/10.1006/mcne.1999.0814

    Article  CAS  PubMed  Google Scholar 

  25. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139(2):267–284. https://doi.org/10.1016/j.cell.2009.09.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ferreira SH, Nakamura M, de Abreu Castro MS (1978) The hyperalgesic effects of prostacyclin and prostaglandin E2. Prostaglandins 16(1):31–37

    Article  CAS  PubMed  Google Scholar 

  27. Khasar SG, McCarter G, Levine JD (1999) Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors. J Neurophysiol 81(3):1104–1112

    Article  CAS  PubMed  Google Scholar 

  28. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413(6852):203–210. https://doi.org/10.1038/35093019

    Article  CAS  PubMed  Google Scholar 

  29. Kandel E, Schwartz JH, Jessell T (2012) Principles of neural sciences, Fifth edn. McGraw-Hill, New York

    Google Scholar 

  30. Woolf CJ, Ma Q (2007) Nociceptors--noxious stimulus detectors. Neuron 55(3):353–364. https://doi.org/10.1016/j.neuron.2007.07.016

    Article  CAS  PubMed  Google Scholar 

  31. Nishiguchi J, Sasaki K, Seki S, Chancellor MB, Erickson KA, de Groat WC, Kumon H, Yoshimura N (2004) Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation. Eur J Neurosci 20(2):474–482. https://doi.org/10.1111/j.1460-9568.2004.03508.x

    Article  PubMed  Google Scholar 

  32. Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA et al (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278(5336):275–279

    Article  CAS  PubMed  Google Scholar 

  33. Wiley RG, Lappi DA (2003) Targeted toxins in pain. Adv Drug Deliv Rev 55(8):1043–1054

    Article  CAS  PubMed  Google Scholar 

  34. Vulchanova L, Olson TH, Stone LS, Riedl MS, Elde R, Honda CN (2001) Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 108(1):143–155

    Article  CAS  PubMed  Google Scholar 

  35. Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12(4–5):256–268. https://doi.org/10.1006/mcne.1998.0719

    Article  CAS  PubMed  Google Scholar 

  36. Hai T, Hartman MG (2001) The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene 273(1):1–11

    Article  CAS  PubMed  Google Scholar 

  37. Albers KM, Woodbury CJ, Ritter AM, Davis BM, Koerber HR (2006) Glial cell-line-derived neurotrophic factor expression in skin alters the mechanical sensitivity of cutaneous nociceptors. J Neurosci 26(11):2981–2990. https://doi.org/10.1523/JNEUROSCI.4863-05.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bogen O, Joseph EK, Chen X, Levine JD (2008) GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. Eur J Neurosci 28(1):12–19. https://doi.org/10.1111/j.1460-9568.2008.06308.x

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309. https://doi.org/10.1038/nrn1078

    Article  CAS  PubMed  Google Scholar 

  40. Malik-Hall M, Dina OA, Levine JD (2005) Primary afferent nociceptor mechanisms mediating NGF-induced mechanical hyperalgesia. Eur J Neurosci 21(12):3387–3394. https://doi.org/10.1111/j.1460-9568.2005.04173.x

    Article  PubMed  Google Scholar 

  41. Delmas P, Hao J, Rodat-Despoix L (2011) Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nat Rev Neurosci 12(3):139–153. https://doi.org/10.1038/nrn2993

    Article  CAS  PubMed  Google Scholar 

  42. Lumpkin EA, Caterina MJ (2007) Mechanisms of sensory transduction in the skin. Nature 445(7130):858–865. https://doi.org/10.1038/nature05662

    Article  CAS  PubMed  Google Scholar 

  43. Löken LS, Wessberg J, Morrison I, McGlone F, Olausson H (2009) Coding of pleasant touch by unmyelinated afferents in humans. Nat Neurosci 12(5):547–548. https://doi.org/10.1038/nn.2312

    Article  CAS  PubMed  Google Scholar 

  44. Perl ER (1996) Cutaneous polymodal receptors: characteristics and plasticity. Prog Brain Res 113:21–37

    Article  CAS  PubMed  Google Scholar 

  45. Arcourt A, Gorham L, Dhandapani R, Prato V, Taberner FJ, Wende H, Gangadharan V, Birchmeier C et al (2017) Touch receptor-derived sensory information alleviates acute pain signaling and fine-tunes nociceptive reflex coordination. Neuron 93(1):179–193. https://doi.org/10.1016/j.neuron.2016.11.027

    Article  CAS  PubMed  Google Scholar 

  46. Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH (2009) Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462(7273):651–655. https://doi.org/10.1038/nature08505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim SE, Coste B, Chadha A, Cook B, Patapoutian A (2012) The role of Drosophila Piezo in mechanical nociception. Nature 483(7388):209–212. https://doi.org/10.1038/nature10801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bégay V et al (2014) Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516(7529):121–125. https://doi.org/10.1038/nature13980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Saeed AW, Pawlowski SA, Ribeiro-da-Silva A (2015) Limited changes in spinal lamina I dorsal horn neurons following the cytotoxic ablation of non-peptidergic C-fibers. Mol Pain 11:54. https://doi.org/10.1186/s12990-015-0060-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Taylor AM, Osikowicz M, Ribeiro-da-Silva A (2012) Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain. Pain 153(6):1311–1319. https://doi.org/10.1016/j.pain.2012.03.023

    Article  CAS  PubMed  Google Scholar 

  51. Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, Nassar MA, Dickenson AH et al (2008) The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 321(5889):702–705. https://doi.org/10.1126/science.1156916

    Article  CAS  PubMed  Google Scholar 

  52. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816–824. https://doi.org/10.1038/39807

    Article  CAS  PubMed  Google Scholar 

  53. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI et al (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288(5464):306–313

    Article  CAS  PubMed  Google Scholar 

  54. Breese NM, George AC, Pauers LE, Stucky CL (2005) Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse. Pain 115(1–2):37–49. https://doi.org/10.1016/j.pain.2005.02.010

    Article  CAS  PubMed  Google Scholar 

  55. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI et al (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21(3):531–543

    Article  CAS  PubMed  Google Scholar 

  56. Tena B, Escobar B, Arguis MJ, Cantero C, Rios J, Gomar C (2012) Reproducibility of electronic Von Frey and Von Frey monofilaments testing. Clin J Pain 28(4):318–323. https://doi.org/10.1097/AJP.0b013e31822f0092

    Article  PubMed  Google Scholar 

  57. Zimmerman A, Bai L, Ginty DD (2014) The gentle touch receptors of mammalian skin. Science 346(6212):950–954. https://doi.org/10.1126/science.1254229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dai Y, Fukuoka T, Wang H, Yamanaka H, Obata K, Tokunaga A, Noguchi K (2004) Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. Pain 108(3):258–266. https://doi.org/10.1016/j.pain.2003.12.034

    Article  CAS  PubMed  Google Scholar 

  59. Honore P, Kage K, Mikusa J, Watt AT, Johnston JF, Wyatt JR, Faltynek CR, Jarvis MF et al (2002) Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 99(1–2):11–19

    Article  CAS  PubMed  Google Scholar 

  60. Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, Subieta A, Van Biesen T et al (2002) A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl Acad Sci U S A 99(26):17179–17184. https://doi.org/10.1073/pnas.252537299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Seino D, Tokunaga A, Tachibana T, Yoshiya S, Dai Y, Obata K, Yamanaka H, Kobayashi K et al (2006) The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint. Pain 123(1–2):193–203. https://doi.org/10.1016/j.pain.2006.02.032

    Article  CAS  PubMed  Google Scholar 

  62. Xu GY, Huang LY (2002) Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J Neurosci 22(1):93–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jarvis MF (2003) Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain. Expert Opin Ther Targets 7(4):513–522. https://doi.org/10.1517/14728222.7.4.513

    Article  CAS  PubMed  Google Scholar 

  64. Aley KO, Messing RO, Mochly-Rosen D, Levine JD (2000) Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci 20(12):4680–4685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Reichling DB, Levine JD (2009) Critical role of nociceptor plasticity in chronic pain. Trends Neurosci 32(12):611–618. https://doi.org/10.1016/j.tins.2009.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cunha TM, Verri WA, Silva JS, Poole S, Cunha FQ, Ferreira SH (2005) A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci U S A 102(5):1755–1760. https://doi.org/10.1073/pnas.0409225102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aley KO, Martin A, McMahon T, Mok J, Levine JD, Messing RO (2001) Nociceptor sensitization by extracellular signal-regulated kinases. J Neurosci 21(17):6933–6939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Coleman RA, Smith WL, Narumiya S (1994) International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 46(2):205–229

    CAS  PubMed  Google Scholar 

  69. Ferreira SH, Nakamura M (1979) I - prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins 18(2):179–190

    Article  CAS  PubMed  Google Scholar 

  70. Aley KO, Levine JD (1999) Role of protein kinase A in the maintenance of inflammatory pain. J Neurosci 19(6):2181–2186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kawabata A (2011) Prostaglandin E2 and pain--an update. Biol Pharm Bull 34(8):1170–1173

    Article  CAS  PubMed  Google Scholar 

  72. Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA (2011) HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333(6048):1462–1466. https://doi.org/10.1126/science.1206243

    Article  CAS  PubMed  Google Scholar 

  73. Hucho TB, Dina OA, Levine JD (2005) Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. J Neurosci 25(26):6119–6126. https://doi.org/10.1523/JNEUROSCI.0285-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Ieda Regina dos Santos Schivo, Sérgio Roberto Rosa, Eleni Luiza Tamburus Gomes, Elizabete Rosa, and Ana Kátia dos Santos for their excellent technical assistance.

Funding

The research leading to these results received funding from the São Paulo Research Foundation (FAPESP) under grant agreements number 2011/19670–0 (Thematic project) and 2013/08216–2 (Centre for Research in Inflammatory Disease), from the University of São Paulo NAP-DIN under grant agreement number 11.1.21625.01.0 and from a CNPq grant number 485177/2012-9. L.G.P. was supported by doctoral fellowship from FAPESP under grant number 2010/04043-8.

Author information

Author notes

  1. Larissa G. Pinto

    Present address: Wolfson Centre for Age-Related Diseases, King’s College London, Guy’s Campus, London, UK

  2. Morena B. Sant’Anna

    Present address: Laboratory of Pain and Signaling, Butantan Institute, São Paulo, Brazil

Authors and Affiliations

  1. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Avenue, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Larissa G. Pinto, Guilherme R. Souza, Ricardo Kusuda, Alexandre H. Lopes, Morena B. Sant’Anna, Fernando Q. Cunha, Sérgio H. Ferreira & Thiago M. Cunha

Authors
  1. Larissa G. Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guilherme R. Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ricardo Kusuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandre H. Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Morena B. Sant’Anna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fernando Q. Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sérgio H. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thiago M. Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thiago M. Cunha.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Sérgio H. Ferreira In memoriam

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pinto, L.G., Souza, G.R., Kusuda, R. et al. Non-Peptidergic Nociceptive Neurons Are Essential for Mechanical Inflammatory Hypersensitivity in Mice. Mol Neurobiol 56, 5715–5728 (2019). https://doi.org/10.1007/s12035-019-1494-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1494-5

Keywords

Search

Navigation